Triiodothyronine Secretion in Early Thyroid Failure: The Adaptive Response of Central Feedforward Control

BACKGROUND: Defined by thyroid-pituitary feedback control, clinical diagnosis of hypothyroidism and hyperthyroidism has become synonymous with TSH measurement. We combined in silico analysis and in vivo data to explore the central influences on thyroidal T3 production. MATERIALS & METHODS: A system of five coupled first-order nonlinear parameterised ordinary differential equations (ODEs) is used to model the feedback control of TSH and TRH by thyroid hormones together with the feedforward control of thyroidal T3 secretion and enzymatic T4-T3 conversion. Dependencies of the stable equilibrium solutions of this ODE system, that is the homeostasis of the underlying physiological process, on the system parameters were investigated whether they accounted for clinical observations. RESULTS: During the modelled transition to hypothyroidism, central control imposed an increasing influence in maintaining serum FT3 levels, compared to peripheral conversion efficiency. Numerical continuation analysis revealed dependencies of T3 production on different elements of TSH feedforward control. While T4-T3 conversion provided the main T3 source in euthyroidism, this was overtaken by increasing glandular T3 secretion when thyroid reserve declined. The computational results were in good agreement with data from untreated patients with autoimmune thyroiditis. CONCLUSIONS: Dependencies revealed in the expression of control differ in thyroid health and disease, using a physiologically based mathematical model of combined feedback-feedforward control of the hypothalamic-pituitary-thyroid regulation. Strong T3-protective mechanisms of the control system emerge with declining thyroid function, when glandular T3 secretion becomes increasingly influential over conversion efficiency. This has wide-ranging implications for the utility of TSH in clinical decision-making.